Pancreatic disorders, particularly diabetes mellitus, constitute a major public health problem, as they affect a sizeable proportion of the population and have a profound negative impact on the overall health and quality of life of those individuals so afflicted. While a variety of pharmaceutical compositions have been developed to compensate for reductions in insulin production brought about by pancreatic deficiency, modifications in lifestyle, such as exercise, adherence to a sensible diet, avoidance of tobacco and moderation of alcohol consumption, can do much to alleviate its effects; therefore, it is desirable to conduct genetic screening to identify individuals who are predisposed toward the development of diabetes and other pancreatic disorders while they are still asymptomatic.
Maturity onset (type II) diabetes mellitus is a highly prevalent disease caused by an imbalance between insulin production by the endocrine pancreatic .beta.-cells and the insulin requirements of peripheral tissues. This results in hyperglycemia and secondary cardiovascular, renal, ocular, and neurological complications. Susceptibility to type II diabetes is generally believed to be inherited as a complex polygenic trait. However, a distinct subset of early onset type II diabetes (maturity onset diabetes of the young: MODY) is transmitted as an autosomal dominant monogenic disorder (Tattersall and Fajans, 1975, Diabetes, 24: 44-53). The identification of genes implicated in MODY can be regarded as an effective strategy to gain insight into the molecular pathogenesis of the more common and complex late onset forms of type II diabetes mellitus. To date, three distinct MODY genetic loci have been identified (Froguel et al., 1992, Nature, 356: 162-164), two of which correspond to transcription factors expressed in pancreatic .beta.-cells [HNF1.alpha. (MODY3) and HNF4.alpha. (MODY1)]. MODY2 is caused by mutations in the glucokinase gene.
Insulin promoter factor-1 (IPF-1) is a transcription factor known to mediate glucose-responsive stimulation of insulin gene expression and is necessary for pancreas development. This homeodomain protein, also known as IDX-1, STF-1 and PDX-1, is critical for development of the pancreas in mice and is a key factor for the regulation of the insulin gene in the .beta.-cells of the endocrine pancreas (Miller et al., 1994, EMBO J., 13: 1145-1156; Leonard et al., 1993, Mol. Endocr., 7: 1275-1283; Ohlsson et al., 1993, EMBO J. 12: 4251-4259; Jonnson et al., 1994, Nature, 371: 606-609; Peshavaria et al., 1994, Mol. Endocr. 8: 806-816; Peers et al., 1994, Mol. Endocr.. 8: 1798-1806). Targeted disruption of the Ipf1 gene encoding IPF-1 in transgenic mice results in a failure of the pancreas to develop (pancreatic agenesis), although heterozygosity for this mutation and the wild-type allele has no apparent deleterious consequence (Jonnson, 1994, supra; Offield et al., 1996, Development, 122: 983-995). An object of the present invention comprises a screening assay by which to assess a patient's risk of developing MODY4, to distinguish between MODY4 and other forms of MODY and to assist in determining the genetic basis for other pancreatic disorders that might result from IPF-1 deficiency.